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MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis

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Item Type:Article
Title:MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis
Creators Name:Alborzinia, H. and Flórez, A.F. and Kreth, S. and Brückner, L.M. and Yildiz, U. and Gartlgruber, M. and Odoni, D.I. and Poschet, G. and Garbowicz, K. and Shao, C. and Klein, C. and Meier, J. and Zeisberger, P. and Nadler-Holly, M. and Ziehm, M. and Paul, F. and Burhenne, J. and Bell, E. and Shaikhkarami, M. and Würth, R. and Stainczyk, S.A. and Wecht, E.M. and Kreth, J. and Büttner, M. and Ishaque, N. and Schlesner, M. and Nicke, B. and Stresemann, C. and Llamazares-Prada, M. and Reiling, J.H. and Fischer, M. and Amit, I. and Selbach, M. and Herrmann, C. and Wölfl, S. and Henrich, K.O. and Höfer, T. and Trumpp, A. and Westermann, F.
Abstract:Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.
Keywords:Cancer, Cancer Therapy, Cell Death, Paediatric Cancer, Animals, Mice
Source:Nature Cancer
ISSN:2662-1347
Publisher:Springer Nature
Volume:3
Number:4
Page Range:471-485
Date:28 April 2022
Official Publication:https://doi.org/10.1038/s43018-022-00355-4
PubMed:View item in PubMed

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